Evaluating Outcomes of Enzalutamide and Abiraterone Co-administration: Insights from the ALLIANCE Trial, Journal Club - Rashid Sayyid & Zachary Klaassen

June 5, 2023

Rashid Sayyid and Zach Klaassen discuss a study on the efficacy of combining enzalutamide and abiraterone in treating metastatic castration-resistant prostate cancer (mCRPC) patients. The study, published in the Journal of Clinical Oncology, posits the potential benefit of using both drugs as they counteract each other's resistance mechanisms. Notably, the drugs have been approved separately by the FDA for use in mCRPC patients. The experts discuss the Alliance Group's recent phase three randomized study, comparing the results of using enzalutamide alone and in combination with abiraterone. Although the combination demonstrated a statistically significant yet minor improvement in radiographic progression-free survival (rPFS), it did not notably enhance overall survival rates. This combination also resulted in higher levels of toxicity and adverse events, leading to the conclusion that enzalutamide alone remains the recommended treatment for mCRPC patients in routine clinical practice.


Rashid Sayyid, MD, MSc, Urologic Oncology Fellow, Division of Urology, University of Toronto, Toronto, Ontario

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

Read the Full Video Transcript

Rashid Sayyid: Hello, everyone. This is Rashid Sayyid. I'm a urologic oncology fellow at the University of Toronto. And along with Zach Klaassen, assistant professor and program director at Augusta University, we'll be discussing the recent publication from the Alliance Group which looked at a randomized phase three study of enzalutamide compared with enzalutamide + abiraterone for mCRPC patients. This study was recently published in the Journal of Clinical Oncology with Dr. Michael Morris as the first author.

So we all know the mechanism of action of abiraterone. It's a cytochrome P450 17 or CYP17 inhibitor, which inhibits testosterone biosynthesis in the testes, the adrenals and the prostate gland. And we know that this drug is FDA approved for mCRPC patients in two settings. In 2011, it was approved first in the post-chemo setting based on the COUGAR 301 trial results. And then in 2012, soon thereafter it was approved in the pre-chemo setting based on the COUGAR 302 results. And as we know, the study showed a radiographic progression-free survival benefit from eight months to 16 and a half months and also an overall survival benefit as we see in the Kaplan-Meier curve to the right with a hazard ratio of 0.75 for overall survival.

Conversely, enzalutamide works a little bit different than abiraterone. It's an androgen receptor inhibitor which inhibits the AR nuclear translocation, subsequent DNA binding and co-activator recruitment. This drug is similarly approved for mCRPC patients in both the post and pre-chemo settings. In 2012, it was approved in the post-chemo setting based on the results of the AFFIRM trial, and then two years afterwards in the pre-chemo setting based on the results of the PREVAIL trial, which showed 12 month rPFS improvements of 65% versus 14% with a hazard ratio .19 in favor of enzalutamide utilization and also showed an overall survival improvement as shown in the Kaplan-Meier curve to the right with a hazard ratio of 0.71 in favor of enzalutamide over placebo.

So why combine the two drugs? What is the rationale for combining these two drugs in this trial? So we know that abiraterone resistance is partly due to antigen receptor upregulation. And so if you have antigen receptor upregulation, it may be of benefit to add an androgen receptor inhibitor to counteract this resistance mechanism, which is what enzalutamide is, an AR inhibitor. And then conversely, enzalutamide resistance by blocking the drug, our body adapts to this by upregulating the production of androgen. And so to mitigate that, in theory, you can use abiraterone, which is an androgen biosynthesis inhibitor, to counteract this resistance mechanism. And so is there potentially a synergistic mechanism of action?

There's been a phase one trial previously that was published in European Neurology Oncology 2020 that looked at the combination of abiraterone and enzalutamide in the phase one trial. And as is common with these trials, it was shown to be safe and that was essentially the objective of a phase one trial. It did not result in any altered pharmacokinetics, meaning that using one drug versus the other did not alter how it was essentially processed by our body. And it showed a favorable PSA response and PFS, progression-free survival, rates. So promising and safe for the combination of abiraterone and enzalutamide. And so the ALLIANCE trial or the A031201 essentially included mCRPC patients with evidence of radiographic metastases as you would expect with an mCRPC as opposed to non-metastatic CRPC. Patients had not received chemotherapy for metastases and they had minimal pain or better. And then patients were randomized in a one-to-one fashion to the first arm, enzalutamide, 160 milligrams PO daily versus Arm B, enzalutamide + abiraterone full dose, we note and prednisone, five milligrams as is common when we administer abiraterone for these patients.

This was a phase three RCT that was conducted by the NCI funded Cooperative Group, Alliance for Clinical Trials in Oncology. The primary outcome of this study was overall survival and the secondary outcomes were the usual suspects of radiographic progression-free survival, PSA response, toxicity and then importantly the authors wanted to see was there an association between rPFS and OS, kind of to assess if rPFS is a good surrogate endpoint for future trial design. Patients all had prostate adenocarcinoma. No small cell or new endocrine differentiation was allowed. No prior antigen receptor signaling inhibitors such as abi, enza-apa darolutamide or steroid use prior to enrollment. Chemotherapy use was allowed only in the neoadjuvant or adjuvant settings. It was not allowed in the mCRPC or mHSPC settings, essentially trying to make this a first-line mCRPC trial.

Again, as mentioned, patients had no significant cancer related pain and no significant lab abnormalities. Patients were randomized in a one-to-one fashion to either enzalutamide full dose, 160 milligrams, versus enzalutamide full dose plus abi full dose with prednisone daily. How were the two drugs administered in the combination arm? In the morning, patients got the enzalutamide with the first dose of prednisone, five milligrams, and then in the evening, patients got abiraterone on an empty stomach along with the second dose of abiraterone. Randomization for these patients was stratified by prior chemo exposure, trying to make sure that the utilization of chemotherapy was well-balanced between the two arms and also prognostic risk groups to make sure that one risk group did not have a higher risk compared to the other.

Treatment, as is typical with these studies, was continued until there was evidence of clinical or radiographic progression. Obviously, if patients had severe toxicity or wanted to withdraw, they were allowed to do so. Progression was classified using the Prostate Cancer Working Group 2 criteria, which was defined as two consecutive PSA increases at least one week apart. You had to have a PSA of 2+ and a four week period of progression after withdrawal of the first generation non-steroidal if receiving them. We don't usually do that as often nowadays, but again, need to remember this trial was conducted or started at least seven to eight years ago.

The target sample size was 1,224 patients. And importantly with these trials, it's not only the number of patients that drives the power and the analysis but also the number of events. So the target number of events for the study was 616 events, which was death given that the primary outcome was overall survival. And this trial had high power, 90% power as opposed to the usual 80% to evaluate a hazard ratio for overall survival of .77 in favor obviously, the combination enzalutamide and abiraterone. And this assumes a median overall survival about three years in control arm as was typical previously at a type one error rate of 2.5%.

The authors use survival analysis of Kaplan-Meier curves, a log rank test as is typical. And this was used to compare the outcomes between the two study arms for time to event outcomes such as survival outcomes. And then the association between radiographic progression-free survival and overall survival was evaluated using three different definitions of progression again to make sure that we assess rPFS as a good surrogate endpoint of overall survival. The authors also performed pharmacokinetic studies and correlative analysis, but the correlative analysis specifically is to be reported separately in a later manuscript. And at this point, I'll turn it over to Zach to delve further into the results, discussion and conclusions of this report.

Zach Klaassen: Thanks so much, Rashid. So this is a consort diagram for this ALLIANCE trial. As you can see here, there was 1,311 patients that were randomly assigned. This includes 657 to enzalutamide alone and 654 to enzalutamide + abiraterone, which made up the efficacy analysis for this trial. This is the baseline characteristics stratified by treatment arms. We can see here that these are well-balanced arms of this trial. The most common age range was 65 to 75 years of age, roughly 40%, majority of these patients had excellent performance status, more than 50% were ECOG 0, roughly 83% of patients in both arms were white, and with regards to risk group, the majority of patients were low risk at just under 50%.

When we look at most common Gleason score, this was Gleason 8 to 10, 57% in the enza alone arm and 54% in the enza + abi arm. Roughly 83 and 82% of patients had bone metastases. 4 and 5% had liver metastases. 11 to 12% had lung metastases. And roughly 50% had nodal metastases. Finally, at the bottom of the table, we can see that 90% of patients had treatment to the primary tumor. 2% had prior chemotherapy. And PSA at the time of trial entry was 23.8 for enzalutamide and 24.3 for enzalutamide + abiraterone.

The next several slides will be Kaplan-Meier curves. We can see the color breakdown here. Enzalutamide alone is in blue. Enzalutamide + abiraterone is in red. This is for overall survival. Very similar median OS, 32.7 months for enzalutamide and 34 point 34.2 months for enza + abi with the hazard ratio 0.89 and a 95% confidence interval of 0.78 to 1.01. So no difference in OS. This is rPFS according to the Prostate Cancer Working Group definition. And we can see here a slight benefit of roughly three months for enza + abiraterone, 24.3 versus 21.3 for enza alone with a hazard ratio of 0.86, 95% confidence interval of 0.76 to 0.97, favoring the enza + abiraterone combination arm. This is rPFS according to the Prostate Cancer Working Group definition plus clinical progression. Again, we see a roughly three month benefit for enza + abiraterone, hazard ratio of 0.87, 95% confidence interval of 0.77 to 0.98. This is rPFS according to Prostate Cancer Working Group definition plus post-treatment radiographic progression. A slight benefit for enzalutamide + abiraterone with a hazard ratio of 0.88, 95% confidence interval of 0.78 to 1.00.

This is the Forest plot for overall survival. Generally, there was no benefit to the combination. We do see a couple of subgroups that may derive or have a signal towards benefit those with ECOG performance status of 1, those with BPI greater than or equal to one and those with bone metastases. Otherwise, no significant benefit in the rest of these subgroups to the enza + abi arm. The authors did look at radiographic progression and clinical progression events in more detail. Generally, to summarize this table, there was very little difference in rPFS or clinical progression events between these two arms. I will highlight that the majority of rPFS events were for soft tissue, 30% in enza arm and 23% in the enza + abiraterone arm. When we go down to clinical progression, we could see that fatigue was actually a little bit higher in the enza alone arm, 49% compared to 41% in the enza + abiraterone arm.

With regards to treatment emergent adverse events, there are several important points to highlight. So on the left is all grade adverse events, on the right is grade three to five separated by each arm. And I've highlighted several important points. So if we look at grade three to five fatigue, 11% for enza + abiraterone compared to only 6% for enzalutamide alone, hypertension grade three to five, 31% for enza + abiraterone compared to 22% enza alone. When we look at AST/ALT increase all grade, 43% for enza + abi compared to 19% for enza alone. And when we look at grade three to five events for AST/ALT increase, 9% for enza + abi compared to 2% for enza alone. Finally at the bottom of this table, total non-hematologic toxicity grade three to five events was higher for enza + abi at 69% compared to 55% for enzalutamide alone.

Just to summarize the pharmacokinetics, this was analyzed in 916 patients and the key takeaway is that the pharmacokinetic clearance of abiraterone was 2.2 to 2.9 folds higher when administered with enzalutamide compared to clearance values of abiraterone alone. So this combination of enza + abi is leading to higher levels of abiraterone in the patients.

So by way of discussion, the Alliance A031201 trial was an adequately designed, NCI funded randomized phase three trial with the gold standard primary endpoint of overall survival. As we showed, the combination of enzalutamide + abiraterone did not significantly prolong overall survival. And although rPFS was three months longer in the combination arm and although this difference was statistically significant, it is of limited clinical meaningfulness given the added toxicity and cost of the combination. One possible reason for lack of effect of the combination approach is the apparent effect of enzalutamide on hepatic clearance of abiraterone and this pharmacokinetic phenomenon may also apply to the metastatic castrate sensitive disease space in the STAMPEDE trial in which ADT + abiraterone seemed to have the same benefit as ADT + abi + enza.

So in conclusion, the combination of enzalutamide + abiraterone and prednisone for first line treatment of mCRPC offered no clinical advantage over enzalutamide alone. The combination was associated with an unfavorable drug-drug interaction that increased abiraterone clearance and with more adverse events. Finally, the combination of enzalutamide + abi is currently not recommended in routine clinical practice. Well, thank you very much for your attention. We hope we enjoyed this Uro Today General Club discussion of this recently published ALLIANCE trial.